H.O.P.E. grows: An academic-public health partnership to reimagine public health services and increase mental health access among socially vulnerable populations.

OBJECTIVE: To illustrate the process of developing and sustaining an academic-public health partnership for behavioral health integration through an expansion of the Aligning Systems for Health (ASfH) framework. STUDY SETTING: Practice-informed primary data (2017-2023) from the Holistic Opportunity Program for Everyone (HOPE) Initiative based in Charlotte, NC. STUDY DESIGN: The unit of analysis in this descriptive case study is inter-organizational, specifically focusing on an academic-public health relationship. We illustrate the partnership process across the ASfH four core areas, including key challenges and insights. DATA COLLECTION: Utilized a Critical Moments Reflection methodology and review of HOPE program data. PRINCIPAL FINDINGS: (1) Formal partnership structures and processes are essential to monitoring the four ASfH core components for on-going system alignment. (2) Aligning systems for health principally involves two ecologies: (i) the health program and (ii) the partnership. The vitality and sustainability of both ecologies require continuous attention and resource investment. (3) Relationships rest at the heart of aligning systems. (4) With comparative advantages in research methods, the academic sector is especially poised to collaborate with healthcare systems and human service organizations to study, develop, implement, and scale evidence-based health interventions. CONCLUSIONS: The academic sector shares overlapping purposes with the public health, healthcare, and social services sectors while providing complementary value. It is a critical sectoral partner in advancing population health and health equity.

Regional White Matter Hyperintensities Relate to Specific Cognitive Abilities in Older Adults Without Dementia.

INTRODUCTION: White matter hyperintensities (WMHs) are magnetic resonance imaging markers of small vessel cerebrovascular disease that are associated with cognitive decline and clinical Alzheimer disease. Previous studies have often focused on global or total WMH; less is known about associations of regional WMHs and cognitive abilities among older adults without dementia. METHODS: A total of 610 older adults with normal cognition (n=302) or mild cognitive impairment (n=308) from the Alzheimer's Disease Neuroimaging Initiative underwent neuropsychological testing and magnetic resonance imaging. Linear regression models examined associations between regional WMH volumes and cognition, adjusting for age, sex, education, apolipoprotein E ε4 allele frequency, and pulse pressure. RESULTS: Among all participants, greater regional WMH volume in all lobes was associated with poorer performance on memory and speed/executive functioning. Among participants with normal cognition, greater temporal and occipital WMH volumes were associated with poorer memory, whereas no regional WMH volumes were associated with speed/executive function. DISCUSSION: Results show that greater regional WMH volume relates to poorer cognitive functioning-even among those with normal cognition. Together with results from previous studies, our findings raise the possibility that WMH may be a useful therapeutic target and/or important effect modifier in treatment or prevention dementia trials.

White Matter Hyperintensity Volume and Amyloid-PET Synergistically Impact Memory Independent of Tau-PET in Older Adults Without Dementia.

BACKGROUND: Alzheimer's disease (AD) and cerebrovascular disease are common, co-existing pathologies in older adults. Whether the effects of cerebrovascular disease and AD biomarkers on cognition are additive or synergistic remains unclear. OBJECTIVE: To examine whether white matter hyperintensity (WMH) volume moderates the independent association between each AD biomarker and cognition. METHODS: In 586 older adults without dementia, linear regressions tested the interaction between amyloid-ß (Aß) positron emission tomography (PET) and WMH volume on cognition, independent of tau-PET. We also tested the interaction between tau-PET and WMH volume on cognition, independent of Aß-PET. RESULTS: Adjusting for tau-PET, the quadratic effect of WMH interacted with Aß-PET to impact memory. There was no interaction between either the linear or quadratic effect of WMH and Aß-PET on executive function. There was no interaction between WMH volume and tau-PET on either cognitive measure. CONCLUSION: Results suggest that cerebrovascular lesions act synergistically with Aß to affect memory, independent of tau, highlighting the importance of incorporating vascular pathology into biomarker assessment of AD.

APOE differentially moderates cerebrospinal fluid and plasma phosphorylated tau181 associations with multi-domain cognition.

Biofluid markers of phosphorylated tau181 (p-tau181) are increasingly popular for the detection of early Alzheimer's pathologic changes. However, the differential dynamics of cerebrospinal fluid (CSF) and plasma p-tau181 remain under investigation. We studied 727 participants from the Alzheimer's Disease Neuroimaging Initiative with plasma and CSF p-tau181 data, apolipoprotein (APOE) ε4 carrier status, amyloid positron emission tomography (PET) imaging, and neuropsychological data. Higher levels of plasma and CSF p-tau181 were observed among APOE ε4 carriers. CSF and plasma p-tau181 were significantly associated with memory, and this effect was greater in APOE ε4 carriers. However, whereas CSF p-tau181 was not significantly associated with language or attention/executive function among ε4 carriers or non-carriers, APOE ε4 status moderated the association of plasma p-tau181 with both language and attention/executive function. These findings lend support to the notion that p-tau181 biofluid markers are useful in measuring AD pathologic changes but also suggest that CSF and plasma p-tau181 have unique properties and dynamics that should be considered when using these markers in research and clinical practice.

Cognitive Heterogeneity and Risk of Progression in Data-Driven Subtle Cognitive Decline Phenotypes.

BACKGROUND: There is increasing recognition of cognitive and pathological heterogeneity in early-stage Alzheimer's disease and other dementias. Data-driven approaches have demonstrated cognitive heterogeneity in those with mild cognitive impairment (MCI), but few studies have examined this heterogeneity and its association with progression to MCI/dementia in cognitively unimpaired (CU) older adults. OBJECTIVE: We identified cluster-derived subgroups of CU participants based on comprehensive neuropsychological data and compared baseline characteristics and rates of progression to MCI/dementia or a Dementia Rating Scale (DRS) of ≤129 across subgroups. METHODS: Hierarchical cluster analysis was conducted on individual baseline neuropsychological test scores from 365 CU participants in the UCSD Shiley-Marcos Alzheimer's Disease Research Center longitudinal cohort. Cox regressions examined the risk of progression to consensus diagnosis of MCI or dementia, or to DRS score ≤129, by cluster group. RESULTS: Cluster analysis identified 5 groups: All-Average (n = 139), Low-Visuospatial (n = 46), Low-Executive (n = 51), Low-Memory/Language (n = 83), and Low-All Domains (n = 46). Subgroups had unique demographic and clinical characteristics. Rates of progression to MCI/dementia or to DRS ≤129 were faster for all subgroups (Low-All Domains progressed the fastest > Low Memory/Language≥Low-Visuospatial and Low-Executive) relative to the All-Average subgroup. CONCLUSION: Faster progression in the Low-Visuospatial, Low-Executive, and Low-Memory/Language groups compared to the All-Average group suggests that there are multiple pathways and/or unique subtle cognitive decline profiles that ultimately lead to a diagnosis of MCI/dementia. Use of comprehensive neuropsychological test batteries that assess several domains may be a key first step toward an individualized approach to early detection and fewer missed opportunities for early intervention.

Tau levels are higher in objective subtle cognitive decline but not subjective memory complaint.

BACKGROUND: The 2018 NIA-AA Alzheimer's Disease (AD) Research Framework states that subtle cognitive decline in cognitively unimpaired individuals can be measured by subjective reports or evidence of objective decline on neuropsychological measures. Both subjective memory complaint (SMC) and objective subtle cognitive decline (Obj-SCD) have been shown to be associated with future cognitive decline and AD biomarkers. We examined whether there are differences in tau PET levels between (a) SMC- vs. SMC+ participants, (b) Obj-SCD- vs. Obj-SCD+ participants, and (c) participants with overlapping vs. discrepant SMC and Obj-SCD classifications. METHODS: Cognitively unimpaired participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 236) were classified at baseline as positive or negative for SMC (SMC- n = 77; SMC+ n = 159) based on the first 12 items of the Cognitive Change Index and/or classified as positive or negative for Obj-SCD (Obj-SCD- n = 173; Obj-SCD+ n = 63) based on previously defined neuropsychological criteria. Analyses of covariance, adjusting for age, sex, APOE ε4 carrier status, and pulse pressure, examined the group differences in tau PET (AV-1451) using a composite standardized uptake variable ratio (SUVR) for regions consistent with Braak stage III/IV. The chi-squared tests examined the tau positivity rates across the groups. RESULTS: Obj-SCD+ participants had higher tau continuous SUVR levels (p = .035, ηp2 = .019) and higher rates of tau positivity (15.8% Obj-SCD- vs. 30.2% Obj-SCD+) than Obj-SCD- participants. Neither tau levels (p = .381, ηp2 = .003) nor rates of tau positivity (18.2% SMC- and 20.1% SMC+) differed between the SMC groups. There was very little agreement between SMC and Obj-SCD classifications (42%; κ = 0.008, p = .862). Participants who were Obj-SCD+ without SMC had the highest tau PET levels and differed from participants who were SMC+ without Obj-SCD (p = .022). Tau levels in participants with both SMC and Obj-SCD did not differ from those with only Obj-SCD (p = .216). Tau positivity rates across the SMC-/Obj-SCD-, SMC+/Obj-SCD-, SMC-/Obj-SCD+, and SMC+/Obj-SCD+ groups were 10.5%, 18.1%, 40.0%, and 25.6%, respectively. CONCLUSION: Participants with Obj-SCD had a greater tau PET burden than those without Obj-SCD, but SMC was not associated with higher tau levels. The combination of SMC and Obj-SCD did not have higher tau levels than Obj-SCD alone. Findings add to the evidence that the Obj-SCD classification is associated with AD biomarkers and faster cognitive decline in ADNI participants, but further work is needed to validate this approach in more representative/diverse cohorts.

Interactive Effects of Pulse Pressure and Tau Imaging on Longitudinal Cognition.

BACKGROUND: Studies have demonstrated that both tau and cardiovascular risk are associated with cognitive decline, but the possible synergistic effects of these pathologic markers remain unclear. OBJECTIVE: To explore the interaction of AD biomarkers with a specific vascular risk marker (pulse pressure) on longitudinal cognition. METHODS: Participants included 139 older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers of tau, amyloid-ß (Aß), and vascular risk (pulse pressure) were assessed. Neuropsychological assessment provided memory, language, and executive function domain composite scores at baseline and 1-year follow-up. Multiple linear regression examined interactive effects of pulse pressure with tau PET independent of Aß PET and Aß PET independent of tau PET on baseline and 1-year cognitive outcomes. RESULTS: The interaction between pulse pressure and tau PET significantly predicted 1-year memory performance such that the combined effect of high pulse pressure and high tau PET levels was associated with lower memory at follow-up but not at baseline. In contrast, Aß PET did not significantly interact with pulse pressure to predict baseline or 1-year outcomes in any cognitive domain. Main effects revealed a significant effect of tau PET on memory, and no significant effects of Aß PET or pulse pressure on any cognitive domain. CONCLUSION: Results indicate that tau and an indirect marker of arterial stiffening (pulse pressure) may synergistically contribute to memory decline, whereas Aß may have a lesser role in predicting cognitive progression. Tau and vascular pathology (particularly in combination) may represent valuable targets for interventions intended to slow cognitive decline.

Objective subtle cognitive decline and plasma phosphorylated tau181: Early markers of Alzheimer's disease-related declines.

INTRODUCTION: Objectively-defined subtle cognitive decline (Obj-SCD) and plasma phosphorylated-tau181 (p-tau181) are promising early Alzheimer's disease (AD) markers. However, associations between Obj-SCD and p-tau181, and their combined prognostic potential, are unknown. METHODS: Baseline and 4-year longitudinal p-tau181 changes were compared across cognitively unimpaired (CU; n = 402), Obj-SCD (n = 199), and mild cognitive impairment (MCI; n = 346) groups. CU and Obj-SCD participants were further classified as p-tau181-positive or negative. RESULTS: CU and Obj-SCD has lower baseline p-tau181 than MCI and did not differ from one another. Longitudinally, Obj-SCD had the steepest p-tau181 increase. Obj-SCD/p-tau181-positive participants had the fastest rates of amyloid accumulation, cognitive decline, and functional decline. CONCLUSIONS: Despite assumptions that cognitive changes invariably follow biomarker changes, early neuropsychological difficulties may emerge before/concurrently with plasma p-tau181 changes. Combining Obj-SCD and p-tau181, two potentially accessible early markers, was associated with the faster declines in AD-related outcomes.

Semantic predictability and adaptation to nonnative speech.

Listeners improve their ability to understand nonnative speech through exposure. The present study examines the role of semantic predictability during adaptation. Listeners were trained on high-predictability, low-predictability, or semantically anomalous sentences. Results demonstrate that trained participants improve their perception of nonnative speech compared to untrained participants. Adaptation is most robust for the types of sentences participants heard during training; however, semantic predictability during exposure did not impact the amount of adaptation overall. Results show advantages in adaptation specific to the type of speech material, a finding similar to the specificity of adaptation previously demonstrated for individual talkers or accents.

Examining the factors that affect structural repetition in question answering.

We present two experiments that examine structural priming in the single-trial phone-call paradigm introduced by Levelt and Kelter (Cognitive psychology, 14 (1), 78-106, 1982). Experimenters called businesses and asked either What time do you close? or At what time do you close? Participants were more likely to produce a prepositional response (At 7 o'clock vs. 7 o'clock) following a prepositional question than following a non-prepositional question. Experiments 1 and 2 attempted to strengthen the priming effect by having the experimenters engage in a brief interaction with the participant before asking the What time…? question. The interactions did not reliably affect the observed priming effect. An analysis across experiments demonstrated that the priming effect found in this paradigm is generally smaller than the average structural priming effect (as reported in Mahowald, James, Futrell, & Gibson, Journal of Memory and Language, 91, 5-27, 2016), but within the range of the effects that are observed in different structural priming paradigms.

Metabolome-wide association study of anti-epileptic drug treatment during pregnancy.

Pregnant women with epilepsy (PWWE) require continuous anti-epileptic drug (AED) treatment to avoid risk to themselves and fetal risks secondary to maternal seizures, resulting in prolonged AED exposure to the developing embryo and fetus. The objectives of this study were to determine whether high-resolution metabolomics is able to link the metabolite profile of PWWE receiving lamotrigine or levetiracetam for seizure control to associated pharmacodynamic (PD) biological responses. Untargeted metabolomic analysis of plasma obtained from 82 PWWE was completed using high-resolution mass spectrometry. Biological alterations due to lamotrigine or levetiracetam monotherapy were determined by a metabolome-wide association study that compared patients taking either drug to those who did not require AED treatment. Metabolic changes associated with AED use were then evaluated by testing for drug-dose associated metabolic variations and pathway enrichment. AED therapy resulted in drug-associated metabolic profiles recognizable within maternal plasma. Both the parent compounds and major metabolites were detected, and each AED was correlated with other metabolic features and pathways. Changes in metabolites and metabolic pathways important to maternal health and linked to fetal neurodevelopment were detected for both drugs, including changes in one­carbon metabolism, neurotransmitter biosynthesis and steroid metabolism. In addition, decreased levels of 5-methyltetrahydrofolate and tetrahydrofolate were detected in women taking lamotrigine, which is consistent with recent findings showing increased risk of autism spectrum disorder traits in PWWE using AED. These results represent a first step in development of pharmacometabolomic framework with potential to detect adverse AED-related metabolic changes during pregnancy.